Mannich reaction introduction, mechanism and applications

1. MANNICH REACTION

2. CONTENTS
• Introduction
• Mechanism
• Applications

3. MANNICH REACTION
Introduction
• The Mannich reaction is aminoalkylation reaction
which involves the condensation of an enolizable
carbonyl compound with the compound containing
active hydrogen with formaldehyde(non-enolizable)
and ammonia or 1 or 2 amines usually as their
hydrochlorides (HCl being used as catalyst) to form
aminomethyl or substituted aminomethyl derivatives is
known as Mannich reaction. The base, called Mannich
base(Alpha,beta-amino carbonyl compound), is usually
isolated as its hydrochloride.
• Aryl amines do not normally respond to this reaction.

4. MANNICH REACTION
Introduction
• With ammonia or primary amines, the
reaction may proceed further since the first
formed Mannich base still contains hydrogen
on the nitogen atom, i.e., active hydrogen.
Hence, 2 amine is preferred for the reaction.

5. MANNICH REACTION
Introduction
• Similarly, three successive reactions with
ammonia give a tertiary amine.
• Thus, with a 1 or 2 amine, the reaction may
proceed further to give a 3 amine.
• The compounds containing active hydrogens
(compounds that can donate proton)which react
include aldehydes, ketones, esters,
phenols,nitroalkanes, - and - methyl pyridines, -
and - methyl quinolines, acetylenes, etc.

6. MANNICH REACTION
Introduction
• Ketones with active hydrogen are more
commonly used. If the compound contains
more than one active hydrogen, all of them
may be substituted by amino methyl groups.

7. MANNICH REACTION
Mechanism

8. MANNICH REACTION
Mechanism

9. MANNICH REACTION
Mechanism
• With unsymmetrical ketones the more highly
alkylated -carbon is substituted by the
aminomethyl group. This is due to the more
acidic character of the hydrogen on the more
highly alkylated carbon and for that matter
due to more facile enolisation.

10. MANNICH REACTION
Applications
1. Many important natural products, especially
alkaloids, have been synthesized by this
reaction. A classical example is Robinson's
synthesis of tropinone by a double Mannich
condensation and subsequent synthesis of
atropine.

11. MANNICH REACTION
Applications

12. MANNICH REACTION
Applications
2. Decomposition to saturated and unsaturated
ketones on reduction and on heating
respectively.
• Quaternary salts give better yield of
unsaturated ketones on heating. The reaction
is useful for introducing vinyl group.

13. MANNICH REACTION
Applications
3. Building up of ring system—The easy
elimination of R2NH from Mannich base has
synthetic applications. Thus, the unsaturated
ketones obtained by heating the quarternary
salts may be used for building ring systems.

14. MANNICH REACTION
Applications
4. The imminium salt, being a strong
electrophile, replaces the active hydrogens of
indole, phenol,nitroalkane, etc., e.g.

15. MANNICH REACTION
Applications
5. Tutocaine, a commercially useful anaesthetic,
is prepared as below.

16. MANNICH REACTION
Applications
• 6. Synthesis of tryptophan—The amino acid,
tryptophan is synthesized from the quaternary
salt of gramine and acetamidomalonic ester.

17. • Sanyal,S.N.;Reactions, Rearrangements and
Reagents,Bharati bhawan P&D, pg-142-145
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